Dysfunctional visual word form processing in progressive alexia

BRAINA JOURNAL OF NEUROLOGY

Dysfunctional visual word form processing inprogressive alexiaStephen M. Wilson,1,2 Kindle Rising,1 Matthew T. Stib,1 Steven Z. Rapcsak1,2 andPelagie M. Beeson1,2

1 Department of Speech, Language and Hearing Sciences, University of Arizona, Tucson, AZ, USA

2 Department of Neurology, University of Arizona, Tucson, AZ, USA

Correspondence to: Stephen M. Wilson, Ph.D.

Department of Speech, Language and Hearing Sciences,

P.O. Box 210071, Tucson, AZ 85721, USA

E-mail: [email protected].

Progressive alexia is an acquired reading deficit caused by degeneration of brain regions that are essential for written word

processing. Functional imaging studies have shown that early processing of the visual word form depends on a hierarchical

posterior-to-anterior processing stream in occipito-temporal cortex, whereby successive areas code increasingly larger and more

complex perceptual attributes of the letter string. A region located in the left lateral occipito-temporal sulcus and adjacent

fusiform gyrus shows maximal selectivity for words and has been dubbed the ‘visual word form area’. We studied two patients

with progressive alexia in order to determine whether their reading deficits were associated with structural and/or functional

abnormalities in this visual word form system. Voxel-based morphometry showed left-lateralized occipito-temporal atrophy in

both patients, very mild in one, but moderate to severe in the other. The two patients, along with 10 control subjects, were

scanned with functional magnetic resonance imaging as they viewed rapidly presented words, false font strings, or a fixation

crosshair. This paradigm was optimized to reliably map brain regions involved in orthographic processing in individual subjects.

All 10 control subjects showed a posterior-to-anterior gradient of selectivity for words, and all 10 showed a functionally defined

visual word form area in the left hemisphere that was activated for words relative to false font strings. In contrast, neither of the

two patients with progressive alexia showed any evidence for a selectivity gradient or for word-specific activation of the visual

word form area. The patient with mild atrophy showed normal responses to both words and false font strings in the posterior

part of the visual word form system, but a failure to develop selectivity for words in the more anterior part of the system. In

contrast, the patient with moderate to severe atrophy showed minimal activation of any part of the visual word form system for

either words or false font strings. Our results suggest that progressive alexia is associated with a dysfunctional visual word form

system, with or without substantial cortical atrophy. Furthermore, these findings demonstrate that functional MRI has the

potential to reveal the neural bases of cognitive deficits in neurodegenerative patients at very early stages, in some cases

before the development of extensive atrophy.

Keywords: progressive alexia; letter-by-letter reading; posterior cortical atrophy; logopenic primary progressive aphasia; visual wordform system

Abbreviations: PCA = posterior cortical atrophy; VWFA = visual word form area

doi:10.1093/brain/awt034 Brain 2013: 136; 1260–1273 | 1260

Received June 13, 2012. Revised December 11, 2012. Accepted December 29, 2013

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IntroductionReading involves a complex mapping from a pattern of light on

the retina to an abstract visual word form that is invariant for

features such as size, location, case and font (Warrington and

Shallice, 1980). Functional imaging studies suggest that this map-

ping depends on a hierarchical posterior-to-anterior gradient of

processing in the ventral visual stream, with successive regions

coding increasingly larger and more complex perceptual attributes

of the letter string (Cohen et al., 2003; Grainger and Whitney,

2004; Dehaene et al., 2005; Vinckier et al., 2007). Collectively,

the cortical network of visual areas that support reading has been

referred to as the visual word form system (Vinckier et al., 2007).

The earlier stages of processing are bilateral; primary visual cortex

represents simple features such as oriented bars, and extrastriate

visual areas extract local contours and then letter shapes. The

culmination of this stream of processing is an abstract visual

word form in a left-lateralized region located in the lateral

occipito-temporal sulcus and/or adjacent fusiform gyrus (Binder

and Mohr, 1992; Cohen et al., 2000, 2002; Molko et al., 2002;

Clarke, 2003; Cohen et al., 2003; Dehaene et al., 2005; Vinckier

et al., 2007; Epelbaum et al., 2008; Dehaene and Cohen, 2011).

This region has been termed the ‘visual word form area’ (VWFA)

(Cohen et al., 2000). Although its functional specificity continues

to be debated (Price and Devlin, 2003, 2011; Dehaene and

Cohen, 2011; Vogel et al., 2012), researchers concur that the

VWFA plays an important role in reading.

Acquired reading deficits are traditionally divided into peripheral

and central alexias. Peripheral alexias involve deficits in mapping

visual inputs to visual word forms, whereas central alexias involve

damage to orthographic representations or the mapping from or-

thography to phonological and/or semantic representations. When

the visual word form system is damaged, words can no longer be

recognized quickly and automatically. Reading is often possible to

some extent, but it is characterized by a slow and effortful serial

strategy referred to as letter-by-letter reading (Dejerine, 1892;

Damasio and Damasio, 1983; Binder and Mohr, 1992;

Beversdorf et al., 1997; Cohen et al., 2003; Leff et al., 2006;

Mani et al., 2008; Pflugshaupt et al., 2009). Although

letter-by-letter reading is generally considered the most archetypal

form of peripheral alexia, it should be noted that many patients

with letter-by-letter reading also exhibit central orthographic pro-

cessing deficits that may affect both reading and spelling

(Behrmann et al., 1998; Rapcsak and Beeson, 2004; Tsapkini

and Rapp, 2010).

Acquired alexia due to neurodegenerative disease is termed

‘progressive alexia’. Its onset is insidious and deficits become pro-

gressively worse over time (Mendez et al., 2007). Acquired per-

ipheral alexias are most commonly associated with the clinical

neurodegenerative syndrome of posterior cortical atrophy (PCA)

(Benson et al., 1988), which usually reflects Alzheimer’s pathology

(Hof et al., 1997; Tang-Wai et al., 2004) though other aetiologies

have been reported (Victoroff et al., 1994). PCA is characterized

by progressive deficits of visual and visuospatial functioning.

Peripheral alexias are a prominent early symptom in most, if not

all cases with PCA, often constituting the first clinical

manifestation of the disease (Benson et al., 1988; McMonagle

et al., 2006). Patients with PCA have been reported to present

with a variety of types of peripheral alexia including not only

letter-by-letter reading, but also neglect alexia, attentional alexia,

and alexia secondary to simultanagnosia (Cogan, 1985; De Renzi,

1986; Benson et al., 1988; Freedman et al., 1991; Freedman and

Costa, 1992; Graff-Radford et al., 1993; Ardila et al., 1997;

Beversdorf and Heilman, 1998; Mendez and Cherrier, 1998;

Mendez et al., 2002; Tang-Wai et al., 2004; McMonagle et al.,

2006; Crutch and Warrington, 2007; Mendez et al., 2007; Crutch

and Warrington, 2009; Giovagnoli et al., 2009; Catricala et al.,

2011; Fragassi et al., 2011). Alexia is typically out of proportion to

any other language deficits that may occur, such as anomia or

transcortical sensory aphasia (McMonagle et al., 2006).

Although progressive peripheral alexia most frequently occurs in

patients with PCA, it is also occasionally seen in cases of primary

progressive aphasia. For instance, several patients with semantic

dementia have been reported with letter-by-letter reading

(Hodges et al., 1992; Patterson and Hodges, 1992; Noble et al.,

2000). However, peripheral alexias are not common in primary

progressive aphasia; more commonly seen are central alexias

involving deficits in linking visual word forms to semantic or

phonological representations (Hodges et al., 1992; Patterson and

Hodges, 1992; Mendez, 2002; Jefferies et al., 2004; Brambati

et al., 2009; Wilson et al., 2009; Henry et al., 2012; Snowden

et al., 2012).

Relatively little is known about the neural substrates of progres-

sive peripheral alexias with letter-by-letter reading. Most patients

with clinically defined PCA have atrophy and/or hypometabolism

of bilateral occipito-parietal and/or occipito-temporal cortex

(Benson et al., 1988; Graff-Radford et al., 1993; Mendez et al.,

2002; Tang-Wei et al., 2004; Whitwell et al., 2007); however,

imaging abnormalities are not apparent in all individuals

(McMonagle et al., 2006). Several cases have been reported in

which alexia was the most prominent symptom and in which at-

rophy and/or hypometabolism were more pronounced in left than

right posterior brain regions (Freedman et al., 1991; Beversdorf

and Heilman, 1998; Giovagnoli et al., 2009; Fragassi et al., 2011).

There have also been suggestions that alexia in PCA may be

related to ventral rather than dorsal pathology (Beversdorf and

Heilman, 1998; Mendez and Cherrier, 1998). However, no struc-

tural or functional imaging studies have been carried out to iden-

tify which regions are specifically responsible for progressive alexia

in PCA. Similarly, in primary progressive aphasia, although several

studies have investigated the neural basis of central alexias

(Brambati et al., 2009; Wilson et al., 2009; Henry et al., 2012),

it is not known which regions are implicated in the occasional

patients with primary progressive aphasia whose alexia includes

a peripheral component.

In this study, we investigated the structural and functional status

of the visual word form system, including the VWFA, in two pa-

tients with progressive alexia and a profile of letter-by-letter read-

ing. One patient was diagnosed with PCA and the other with

logopenic variant primary progressive aphasia. We used a func-

tional MRI paradigm that was optimized to detect the

posterior-to-anterior gradient of selectivity for word forms, culmi-

nating in word-specific activity in the VWFA, in every individual

Visual word form processing in progressive alexia Brain 2013: 136; 1260–1273 | 1261


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healthy control participant. We hypothesized that the visual word

form system would be functionally abnormal in the two patients

with progressive alexia, and by comparing the patients to healthy

control subjects, we sought to characterize the nature of any func-

tional abnormalities.

Previous functional imaging studies of patients with

letter-by-letter reading due to stroke or surgical resection have

revealed abnormal or absent neural activation when the VWFA

is damaged or disconnected from its visual inputs (Cohen et al.,

2000, 2003, 2004; Henry et al., 2005; Gaillard et al., 2006;

Epelbaum et al., 2008; Ino et al., 2008; Tsapkini et al., 2011).

All of these cases had frank structural damage to the visual word

form system. In contrast, although our two patients had different

degrees of atrophy in the visual word form system, no regions

were completely destroyed, raising the question of whether

functional abnormalities can be identified in such cases.

Materials and methods

ParticipantsTwo individuals with progressive alexia participated in the study. Both

were male, and aged 71 and 74, respectively, when they were

scanned. Before scanning both patients completed a comprehensive

battery of language, neuropsychological and reading evaluations,

described below.

Control data for the functional imaging study were acquired from

10 healthy control participants who were primarily recruited from

newspaper advertisements or flyers. These included five males and

five females, with a mean age of 67 years (range: 50–77). In particu-

lar, there were four control males who were similar in age (72, 74, 75

and 77 years) to the two patients.

As control subjects for voxel-based morphometry, we used 9 of

these 10 control subjects (the youngest, aged 50, was not used),

plus an additional 13 age-matched control subjects who had been

scanned on the same scanner for a different study, for a total of 22

control subjects. These included nine males and 13 females, with a

mean age of 71 years (range: 63–77).

All participants gave written informed consent, and were compen-

sated for taking part in the study. The study was approved by the

University of Arizona Institutional Review Board.

Patient J: Case history and evaluationsPatient J was a left-handed male who was first seen in November

2010, at which time he was 70 years old. He had a masters degree

in Fine Arts, had worked as an artist and art teacher, and continued to

work part-time facilitating art classes. He described a 4 to 5-year his-

tory of progressive reading difficulties.

Because Patient J was left-handed, we used a standard clinical lan-

guage mapping paradigm (picture naming) to determine whether his

language areas were left-lateralized. This study revealed clear left lat-

eralization for language processing (Supplementary Fig. 1). Because

lateralization for reading tends to match lateralization for spoken lan-

guage (Van der Haegen et al., 2012), it is reasonable to assume that in

Patient J, reading would probably also have been premorbidly

left-lateralized.

Patient J’s spoken language was largely intact (Table 1). In conver-

sation, his output was fluent but characterized by mild anomia. In

formal testing, this was reflected in a score of 46 out of 60 on the

Boston Naming Test. His comprehension of conversational speech was

very good but there was a mild deficit on formal testing of single word

comprehension; he made three semantic errors on spoken

word-picture matching (PALPA 47); in each case, he chose

semantically-related foils, e.g. he chose ‘tiara’ in response to ‘crown’.

He did not show any significant cognitive, executive or memory

deficits (Table 1). He performed poorly only on the Trail Making

Test, which was presumably due to the fact that this test requires

reading of letters and digits. He exhibited only mild visuospatial def-

icits; he performed well on copy and delayed copy of a modified

Rey-Osterrieth figure (Fig. 1B and C) and well on face matching.

However, he missed 3 of 10 items on the number location subtest

from the Visual Object and Space Perception battery (VOSP)

(Warrington and James, 1991), in which participants are asked to

identify which of 16 digits in a square correspond to the location of

a dot in an adjacent square.

Patient J was severely alexic (Table 2). Although he was highly

educated, he was no longer reading at all in daily life. He was com-

pensating through the use of books on tape and a computerized read-

ing program. He had deficits at the single letter level, with errors on

case matching, letter naming, and matching spoken-to-written letters

(Table 2). He read single words extremely slowly with a letter-by-letter

strategy, subvocally mouthing the individual letter names before even-

tually producing a response. His reading time increased as a function

of word length (Fig. 2), a typical pattern in letter-by-letter readers.

Because his single letter naming was error-prone, his letter-by-letter

strategy was often not successful; overall, he read 70% of words and

50% of pseudowords correctly. His most frequent error types were

visually similar words (46%, e.g. ‘stale’ for ‘slate’, ‘bride’ for ‘bribe’,

‘circus’ for ‘circuit’), probably reflecting his deficits at the single letter

level. Other frequent error types were lack of any response (33%) and

unrelated words (17%, e.g. ‘step’ for ‘chef’, ‘huge’ for ‘laugh’).

Paragraph reading was extremely slow. Patient J took 202 s to read

the first two lines of a second grade level passage (18 words, 11.2 s

per word), and he read only 11 of the 18 words correctly.

Patient J’s written spelling was also impaired; he spelled 80% of

regular real words, 60% of irregular real words, and 85% of pseudo-

words correctly. Direct copy of single words was good (96% letters

correct), whereas case conversion was poor (58% correct), suggesting

an allographic impairment, i.e. an impairment in mapping graphemes

to letter shapes.

We evaluated Patient J again in June 2011, 7 months later. His anomia

had progressed only slightly; he scored 42 out of 60 on the Boston

Naming Test. In contrast, his reading was now dramatically worse.

He read only 28% of words and 5% of pseudowords correctly. His

most common error type was not to respond (73%, e.g. ‘I don’t

know’), followed by visually similar words (22%, e.g. ‘dump’ for

‘bump’, ‘comfort’ for ‘compact’). However, testing in the oral modality

revealed strikingly spared orthographic knowledge. He was able to rec-

ognize 98% of words that were spelled out loud for him, and 90% of

pseudowords.

Patient J’s written spelling had further deteriorated; he now spelled

only 55% of regular real words, 33% of irregular real words, and 65%

of pseudowords correctly. However, he performed much better in oral

testing, correctly spelling out loud 95% of regular words, 70% of

irregular words, and 100% of pseudowords. The superior performance

in oral spelling suggests a significant allographic impairment, whereas

the pattern of surface agraphia in both modalities suggested mild

damage to central orthographic representations.

In summary, Patient J presented with severe progressive alexia that

was predominantly peripheral in nature, as evidenced by his very slow

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and error-prone letter-by-letter reading. In addition, he showed a sig-

nificant allographic impairment and mild damage to central ortho-

graphic representations. Patient J met criteria for the clinical

syndrome of PCA (Tang-Wei et al., 2004). We scanned him in June

2011, shortly after this second evaluation.

Patient B: Case history and evaluationPatient B was a right-handed male who was first seen in June 2010, at

which time he was 73-years-old. He had an eighth grade education,

had worked as a construction foreman, and was the owner of a

company involved in the mining industry. He described an

�18-month history of difficulty expressing himself, which he first

noticed as a difficulty in telling jokes, and progressive reading difficul-

ties over the same period.

His spoken language was characterized by prominent anomia, cir-

cumlocutions, and retracings, and mild comprehension difficulties were

evident in conversation. Language testing resulted in a clinical diagno-

sis of logopenic progressive aphasia (Gorno-Tempini et al., 2011),

supported by anomia in spontaneous speech and confrontation

naming, impaired repetition, and preserved single word comprehen-

sion, motor speech, and grammatical function (Table 1).

Table 1 Language and neuropsychological measures in the two progressive alexic patients

Patient J

Nov 2010 June 2011 Patient B

Diagnosis Progressive alexia Progressive alexia

and mild anomia and logopenic PPA

Age 70 71 73

MMSE (/30) 27 25 20

Handedness left-handed right-handed

Language measures

Western Aphasia Battery Aphasia Quotiant (/100) 97.5 — 82.2

WAB classification Anomic — Anomic

Content (/10) 10 — 9

Fluency (/10) 10 — 8

Comprehension (/10) 9.85 — 9.8

Repetition (/10) 10 — 7.4

Naming (/10) 8.9 — 6.9

Boston naming test (/60) 46 42 22

Phonemic verbal fluency (generate words starting with d) 10 10 7

Semantic verbal fluency (generate animal names) 9 7 11

Pyramids and Palm Trees (pictures) 52 51 45

Pyramids and Palm Trees (written) discontinued too impaired discontinued

Spoken word-picture match (PALPA 47, 5AFC, /40) 37 34 40

Arizona Phonological Battery (/100) 94 — 45

Cognitive/Executive/Memory

Raven’s Progressive Coloured Matrices (/36) 31 31 21

Trail Making Test A* 81 s — 45 s

Trail Making Test B* 4300 s — discontinued

Digits forward 8 + 7 5

Digits backwards 5 3 —

Visuospatial tests**

Modified Rey-Osterrieth copy (/17) — 13 13

Modified Rey-Osterrieth delayed copy (/17) — 13 6

Modified Rey-Osterrieth recognition (yes/no) — yes yes

Number location (VOSP) (/10) — 7 8

Face matching (CATS) (/12) — 11 11

MMSE = Mini-Mental State Examination (Folstein et al., 1975); WAB = Western Aphasia Battery (Kertesz, 1982); PALPA = Psycholinguistic Assessments of LanguageProcessing in Aphasia (Kay et al., 1992); VOSP = number location subtest from the Visual Object and Space Perception battery (Warrington and James, 1991); CATS = facematching subtest from the Comprehensive Affect Testing System (Froming et al., 2006).Boston Naming Test (Kaplan et al., 1983); Pyramids and Palm Trees (Howard and Patterson, 1992); Arizona Phonological Battery (Rapcsak et al., 2009); Raven’s

Progressive Colored Matrices (Raven et al., 1990); modified Rey-Osterrieth figure copy and recall (Possin et al., 2011).— = not tested.5AFC = 5-alternative forced choice.* Performance on the Trail Making Test was presumably compromised by reading deficits. Normal performance on Trails A in this age range is 40 � 14 s (education4 12 years, as for Patient J) or 42 � 15 s (education4 12 years, as for Patient B). Normal performance on Trails B is 86 � 24 s (education4 12 years) or 110 � 35 s(education4 12 years) (Tombaugh, 2004).** Visuospatial tests were performed several months later than the other tests.



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Table 2 Orthographic, reading, writing and spelling measures in the two progressive alexic patients

Patient J

Nov 2010 June 2011 Patient B

Single letter tasks

Mirror reversal (PALPA 18, 2AFC, /36) 35 35 32

Case matching (PALPA 19/20, 2AFC, /52) 47 46 37

Letter naming (PALPA 22, /26) 20 17 —

Spoken letter-written letter match (PALPA 23, 4AFC, /26) 23 22 21

Reading

Lexical decision, illicit foils (PALPA 24, 2AFC, /60) 51 49 54

Lexical decision, plausible foils (PALPA 25, 2AFC, /60) discontinued too impaired 36

Orthographic choice (2AFC, /40) 22 too impaired 30

Oral reading of regular words (ABRS) (/40) 31 13 7

Oral reading of irregular words (ABRS) (/40) 25 9 9

Oral reading of pseudowords (ABRS) (/20) 10 1 0

Oral ‘reading’ of regular words spelled out loud (/40) — 39 —

Oral ‘reading’ of irregular words spelled out loud (/40) — 39 —

Oral ‘reading’ of pseudowords spelled out loud (/20) — 18 —

Written word-picture match (PALPA 48, 5AFC, /40) 37 23 29

Writing and spelling

Direct copy of single words (% letters correct) 96% 87% 90%

Case conversion (/52) 30 30 37

Written spelling of regular words (ABRS) (/40) 32 22 12

Written spelling of irregular words (ABRS) (/40) 24 13 5

Written spelling of pseudowords (ABRS) (/20) 17 13 2

Oral spelling of regular words (ABRS) (/40) — 38 —

Oral spelling of irregular words (ABRS) (/40) — 28 —

Oral spelling of pseudowords (ABRS) (/20) — 20 —

PALPA = Psycholinguistic Assessments of Language Processing in Aphasia (Kay et al., 1992); ABRS = Arizona Battery for Reading and Spelling (Henry et al., 2007; Rapcsaket al., 2009; Beeson et al., 2010).Control subjects make only occasional sporadic errors and are at ceiling for all measures (Beeson et al., 2010).— = not tested.nAFC = n-alternative forced choice.

Figure 1 Preserved figure copy and delayed copy in the

two patients with progressive alexia. (A) The modified

Rey-Osterrieth figure (Possin et al., 2011). (B) Patient J’s copy of

the figure. (C) Patient J’s delayed copy of the figure after 10 min.

(D) Patient B’s copy of the figure. (E) Patient B’s delayed copy of

the figure after 10 min.

Figure 2 Reading time increased as a function of word length

in Patient J, a pattern that is characteristic of letter-by-letter

reading.



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Mr. B showed moderate cognitive deficits, as evidenced by poor

performance on Raven’s progressive coloured matrices (Table 1). He

performed poorly on the Trail Making Test but, as noted above, this

test requires reading of letters and digits. He exhibited only mild visuo-

spatial deficits; he performed well on copy and moderately well on

delayed copy of a modified Rey-Osterrieth figure (Fig. 1D and E). He

missed 2 of the 10 items on the number location subtest from the

Visual Object and Space Perception battery, but he did well on face

matching.

Patient B reportedly had never been much of a reader, but he had

read the Bible and trade magazines. He described reading less and less

as he had found it becoming increasingly difficult. Patient B’s reading

was severely impaired (Table 2), with deficits at the single letter level

evident in errors on discrimination of mirror-reversed letters, case

matching, and case conversion. He employed a laborious

letter-by-letter reading strategy that was often unsuccessful due to

his difficulties in the identification of individual letters. The following

examples are typical of his attempts to read single words:

(1) [target: reach] B R E A T H, berneath, bearth, I dunno, that’s

not it

(2) [target: shove] S H O P E sharp, no

(3) [target: choir] cough, C O U M D, cough, that don’t sound right,

cough, C O U, no that’s not C O, C H O I R, cough, no, it’s C O

U something, C H O I R.

Overall, single words were read correctly just 20% of the time, and no

pseudowords were read correctly. The most common error types were

unrelated words (30%, e.g. ‘touch’ for ‘doubt’) and visually similar words

(22%, e.g. ‘change’ for ‘charge’). Too few of his responses were correct

to permit the calculation of reaction time.

Patient B was generally unable to pronounce words that were

spelled out loud for him, but this was not formally tested (note that

the phonological short-term memory deficits of logopenic primary pro-

gressive aphasia would make this challenging even if orthographic

representations were intact). Written spelling was also very poor for

both words and pseudowords.

In sum, patient B showed severe progressive alexia with a significant

peripheral component, as evidenced by his slow and error-prone

letter-by-letter reading. His spelling impairment for both words and

pseudowords indicated damage to lexical-semantic and sublexical spel-

ling mechanisms. In addition, Patient B demonstrated prominent

spoken language deficits, meeting diagnostic criteria for logopenic pri-

mary progressive aphasia (Gorno-Tempini et al., 2011). We scanned

Patient B �1 year after we first saw him, in June 2011.

Functional magnetic resonance imagingexperimental designThe aim of our functional imaging study was to determine whether the

visual word form system was functionally normal in the two patients

with progressive alexia, therefore it was important to optimize our

paradigm such that the functional organization of the visual word

form system could be robustly mapped in each individual healthy con-

trol participant. Otherwise a seemingly abnormal pattern in the pa-

tients might just reflect interindividual variability, and would be difficult

to interpret. Pilot studies suggested that four design features were

important to reliably map the visual word form system: (i) a block

design to maximize signal to noise; (ii) a control condition closely

matched for low-level visual features; (iii) a rapid presentation rate;

and (iv) an attentionally demanding non-linguistic task. It is likely that

these last two features minimize semantic processing and other higher

level processing of the stimuli, and thus are more effective in revealing

lower level processes, which are more consistent across subjects than

higher level processes. Rapid presentation rates and attentionally de-

manding tasks have been used in previous studies aimed at mapping

response selectivity in occipito-temporal cortex (Vinckier et al., 2007).

We used false font strings rather than non-word orthographic strings

as the control condition, because activation levels for non-word strings

depend heavily on the orthographic plausibility of the non-word

strings. Implausible non-words behave like false fonts, whereas

plausible non-words produce similar levels of activity to real words

(Vinckier et al., 2007).

Participants were scanned with functional MRI as they viewed

blocks of rapidly presented words, false font strings, or a fixation

crosshair, while performing an attentionally demanding non-linguistic

task. Each block was 20 s long, and in each run there were six repe-

titions of each of the three conditions, presented in pseudorandom

order, for a total run length of 6 min, plus 8 s to acquire four additional

volumes that were discarded. Participants completed two runs each,

except for one control participant, who completed only one run.

The stimulus words were nouns and adjectives selected from the

Medical Research Council database (Coltheart, 1981). They were all

six letters long and medium frequency, with Kucera-Francis frequen-

cies ranging from 10 to 110. Proper names and some emotive words

were excluded. Words were shown in Times New Roman font, all

capitals, centred on a fixation cross. Words were presented in white

on a grey background for 100 ms, then a white fixation cross was

displayed for 200 ms, then the next word was presented. There

were 67 words in each 20-s block.

The false font stimuli were created using letters from alphabetic

orthographies other than English. These stimuli were presented with

the same timing and visual parameters as the words.

The task was to detect occasional words or false font strings pre-

sented in red instead of white, and then press a button on a response

pad as quickly as possible. These catch trials were presented pseudo-

randomly in four of the six word blocks, and four of the six false

font blocks.

Participants were familiarized with the stimuli and practiced the task,

before being placed in the scanner.

Neuroimaging protocolParticipants were scanned as they lay supine in a General Electric 3 T

HD Signa Excite scanner at the University of Arizona Medical Centre.

They viewed the stimuli through magnetic resonance-compatible gog-

gles (Resonance Technology, Inc), and wore padded headphones and

earplugs to attenuate scanner noise.

For anatomical reference and registration, a T1-weighted 3D spoiled

gradient recalled inversion recovery sequence was acquired with

the following parameters: 160 sagittal slices; slice thickness = 1 mm;

field of view = 256 � 256 mm; matrix = 256 �256 mm; repetition

time = 7.5 ms; echo time = 3.0 ms; inversion time = 500 ms; flip

angle = 15�.

For the functional imaging paradigm, 184 blood oxygen level-

dependent T2*-weighted volumes were acquired using a single-shot

spiral pulse sequence (Glover and Law, 2001) with the following par-

ameters: 30 anterior commissure/posterior commissure-aligned axial

slices in sequential order; slice thickness = 4 mm with no gap; field of

view = 240 � 240 mm; matrix = 64 � 64; repetition time = 2000 ms;

echo time = 30 ms; flip angle = 90�.

Visual stimuli were presented with PsychToolbox 3.0.8 (Brainard,

1997; Pelli, 1997) running under MATLAB 7.11 (Mathworks) on a

Windows PC.



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Voxel-based morphometryThe T1-weighted structural images were bias-corrected, segmented

into grey matter, white matter and CSF, and normalized to MNI

space using the unified segmentation algorithm in SPM (version

SPM5; http://www.fil.ion.ucl.ac.uk/spm; Ashburner and Friston,

2005). Grey matter and white matter probability maps were scaled

by Jacobians, smoothed with a Gaussian kernel of 10 mm full-width

half-maximum, then summed together to obtain a map of brain par-

enchyma (Wilson et al., 2010). Each of the two patients was com-

pared to the 22 control subjects, with age, sex and total intracranial

volume included as covariates. Statistical maps were thresholded at

voxelwise P5 0.005, with a minimum cluster size of 1500 mm3.

Functional magnetic resonance imagingdata analysisThe functional imaging data were preprocessed with AFNI (version

2011-06-22; http://afni.nimh.nih.gov/afni; Cox, 1996). The data

were corrected for slice timing differences, realigned to account for

head movement, smoothed with a Gaussian kernel of 4 mm full-width

half-maximum, high pass filtered (cut-off = 0.006 Hz) and detrended

(Legendre polynomials of order up to and including two). A general

linear model was fit at each voxel using the ‘fmrilm’ procedure from

FMRISTAT (version 2006-06-02; http://www.math.mcgill.ca/keith/

fmristat; Worsley et al., 2002), modelling temporal autocorrelation

as an autoregressive process of degree one.

The design matrix contained one explanatory variable for word

blocks and one for false font blocks, each convolved with a

canonical haemodynamic reference function modelled as a difference

of two gamma functions. Six head motion parameters, slow drift par-

ameters, and the global whole-brain signal were included as covariates

of no interest. Each subject’s two runs were combined with a fixed

effects model using the ‘multistat’ procedure from FMRISTAT.

Functional images were initially coregistered to structural images

using SPM5, then manually realigned for greater accuracy.

Anatomical images were transformed to MNI space with SPM5, and

this transformation was then applied to the statistical images.

To identify the VWFA in each individual subject, we contrasted

words to false font strings at voxelwise P5 0.05, masked by the con-

trast of words to fixation at P5 0.0001 (cf. Glezer et al., 2009). We

considered only clusters with a centre of mass within 15 mm of the

published VWFA coordinates of (–42, –57, –15) (Cohen et al., 2002).

Whole brain random effects group analyses were carried out after

applying a second smoothing kernel (6 mm full-width half-maximum)

to the individual effect size images. To identify the VWFA in the 10

control subjects, we contrasted words to false font strings. This ana-

lysis was thresholded at voxel-wise P5 0.005 and corrected for mul-

tiple comparisons at P5 0.05 based on cluster extent (Worsley et al.,

1996). To identify regions where the two patients showed less activa-

tion than the 10 control subjects, we compared the contrast of words

to false font strings between the patients and control subjects using a

two-sample t-test with pooled variance. This analysis was thresholded

at voxelwise P5 0.005, then corrected for multiple comparisons

(Friston et al., 1997) based on the extent of the closest cluster to

the published coordinates of the VWFA, which was the region

hypothesized to show reduced activation in patients.

Previous studies have demonstrated a posterior-to-anterior gradient

of visual word form processing in the ventral visual stream, with suc-

cessively anterior regions increasingly selective for words (Vinckier

et al., 2007). To identify this selectivity gradient in each individual

subject, we created images showing the signal for false font strings

as a proportion of the signal for words, in regions that were active for

words versus fixation at P5 0.0001. We also plotted the mean signal

for words and false font strings in occipito-temporal cortex in each

hemisphere as a function of y coordinate (i.e. posterior-to-anterior), by

averaging across a region of interest defined by the control group

activation for words versus rest thresholded as described above (vox-

elwise P5 0.005 and corrected for multiple comparisons at P5 0.05).

Results

Voxel-based morphometryVoxel-based morphometry showed that Patient J had very mild

atrophy of the left posterior inferior temporal gyrus, and widening

of the left sylvian fissure (Fig. 3A, Table 3).

Patient B had much more extensive atrophy of the left inferior

and middle temporal gyri, the left fusiform gyrus, the white matter

underlying these regions, and a smaller region of the right poster-

ior inferior temporal gyrus (Fig. 3B, Table 3).

Behavioural data collected duringfunctional magnetic resonance imagingControl subjects responded to 90.5% � 15.8% (SD) of the catch

trials (occasional words or false font strings coloured red instead of

white). Patient J responded to 87.5% of the catch trials, and

Patient B responded to 100% of the catch trials. Most participants

also made occasional false positive responses.

Functional magnetic resonance imagingAll 10 control subjects showed a VWFA that responded more to

words than false font strings according to our criteria (Fig. 4A–C,

Table 4). For the more basic contrasts of words versus fixation and

false font strings versus fixation, all control subjects showed bilat-

eral occipito-temporal activation (Fig. 4A–C).

Unlike the control subjects, neither of the two patients with

progressive alexia showed a VWFA according to our criteria

(Fig. 4D and E, Table 4). For the more basic contrasts relative to

fixation, the two patients differed from one another. Patient

J showed typical robust bilateral occipito-temporal activation for

both of these contrasts (Fig. 4D). Patient B showed much weaker

activation for these contrasts, with more activity in the right than

the left hemisphere (Fig. 4E).

We next checked whether loosening our criteria for the VWFA

(i.e. words versus false font strings P50.05, words versus fixation

P50.0001, within 15 mm of published coordinates) would reveal

any evidence for a VWFA in either patient. For Patient J, there

were two single voxels meeting the voxel-wise criteria in left

occipito-temporal cortex; however, the closest to the VWFA was

27 mm away at (–52, –82, –14). In right occipito-temporal cortex

there was a cluster of 39 voxels with centre of mass (41, –57, 2),

which is 17 mm from the right hemisphere homologue of the

VWFA. We then examined the contrast of words versus false

fonts without the mask of words versus rest, and observed a clus-

ter of 44 voxels with centre of mass (–60, –56, –11), which is



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18 mm from the VWFA. However, activation at that location was

slightly negative for all words relative to rest, suggesting that the

cluster arose due to a deactivation for false font strings. A failure

to activate for words relative to rest is inconsistent with the re-

sponse properties of the VWFA. For Patient B, there were no

voxels meeting the voxel-wise criteria in left occipito-temporal

cortex. In right occipito-temporal cortex there were a few scat-

tered voxels meeting the voxel-wise criteria, but none were close

to the right homologue of the VWFA; the closest was located at

(–40, –72, –2), which is 20 mm from the right hemisphere homo-

logue of the VWFA. We then examined the contrast of words

versus false fonts without the mask of words versus rest, and

observed a small cluster of nine voxels with centre of mass

(–50, –43, –10), which is 17 mm from the VWFA. But activation

at that location was slightly negative for all words relative to

rest, inconsistent with the response properties of the VWFA.

In summary, neither patient showed any activation resembling a

typical VWFA, even when the criteria were relaxed.

We next performed a whole-brain random effects analysis con-

trasting words to false font strings in the 10 control subjects. The

VWFA was the only region activated (centre of mass: –43, –50, –18;

extent = 6312 mm3; corrected P50.001) (Fig. 5A). We then

directly compared the two patients to the 10 control subjects. The

patients showed significantly less activation than control subjects

in the VWFA (centre of mass: –39, –45, –19; extent = 1000 mm3;

corrected P = 0.034) (Fig. 5B). This was the largest cluster observed,

and no other clusters reached significance.

To reveal the anticipated posterior–anterior gradient of selectiv-

ity for words, we plotted the signal to false font strings as a pro-

portion of the signal to words, in regions that were active for

words versus fixation (Fig. 6). We found evidence for this gradient

in each of the 10 control subjects (Fig. 6A–J). There was some

individual variability, for instance, Control Subject 4 (who was

left-handed) showed a typical gradient in the left hemisphere,

but an even stronger gradient in the right hemisphere; Control

Subject 5 showed rather weak activity for both conditions relative

to rest; and Control Subject 9 showed an additional word-selective

region more posteriorly. However, despite this variability, left

hemisphere posterior-anterior gradients were evident in all control

subjects.

In contrast, neither of the two patients with progressive alexia

exhibited a posterior-anterior gradient of selectivity for words

(Fig. 6K and L). Both patients had small regions in the right hemi-

sphere that were selective for words at P50.05, but in both cases

these were considerably dorsal to the right hemisphere homologue

of the VWFA (Fig. 6K and L).

We also plotted the mean signal for words and false font strings

in occipito-temporal cortex in each hemisphere as a function of

Figure 3 Structural images of the two progressive alexic

patients. Regions of tissue loss as revealed by voxel-based

morphometry (voxel-wise P50.005, minimum cluster

extent = 1500 mm3) are shown with red outlines (white in

printed version). (A) Patient J showed mild atrophy of the left

posterior inferior temporal gyrus. (B) Patient B showed much

more extensive atrophy of left temporal cortex.

VBM = voxel-based morphometry.

Table 3 Voxel based morphometry showing tissue loss inthe two progressive alexic patients

Brain region MNI coordinates Max t Extent(mm3)

x y z

Patient J

Left posteriorinferior temporalgyrus

�56 �55 �16 4.75 1680

Left sylvian fissure(widening)

�40 2 2 4.72 5880

Patient B

Left inferior andmiddle temporalgyri and fusiformgyrus

�44 �40 �9 9.67 80032

Right posteriorinferior temporalgyrus

57 �58 �15 5.20 2368

Thresholded at voxel-wise P50.005, cluster extent41500 mm3. Extent is thesize of the region in which there was significant tissue loss (voxel-wise P5 0.005)compared with control subjects.



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y coordinate (i.e. posterior-to-anterior) (Fig. 6). This analysis high-

lighted a notable difference between the two patients. Patient

J showed normal responses to both words and false font strings

in posterior occipito-temporal cortex, but unlike control subjects,

he showed no emergence of selectivity for words more anteriorly.

In fact, he showed somewhat less activity for words than false

font strings in the vicinity of the VWFA. In contrast, Patient B

showed minimal activation for either words or false font strings

in any part of occipito-temporal cortex. In this respect, Patient B

differed from Patient J and the control subjects, all of whom

showed robust responses for both words and false font strings

relative to rest.

Figure 4 Functional identification of the visual word form area. (A, B and C) In three typical control subjects, viewing words or false font

strings relative to fixation activated bilateral occipital and posterior temporal regions (voxel-wise P50.0001). The contrast of words

versus false font strings (voxel-wise P50.05) masked by the contrast of words versus rest (voxel-wise P50.0001) revealed the VWFA in

each of the 10 control participants. (D) Patient J showed typical bilateral occipito-temporal activation for words or false font strings relative

to fixation, however there were no regions activated for words versus false font strings. (E) Patient B showed weak right-lateralized

activation for words or false font strings relative to fixation, and no regions activated for words versus false font strings.

Table 4 Localization of VWFA with functional MRI

Subject MNI coordinates of VWFA Distance Max t Extent

x y z (mm) (mm3)

Control 1 �37 �45 �23 15 2.89 928

Control 2 �44 �54 �16 4 5.25 3432

Control 3 �45 �56 �9 6 4.05 2704

Control 4 �35 �45 �20 15 2.90 616

Control 5 �45 �56 �15 3 2.34 96

Control 6 �41 �60 �12 4 3.72 4328

Control 7 �51 �51 �14 11 5.45 3416

Control 8 �42 �52 �13 6 5.99 3184

Control 9 �43 �52 �12 6 6.56 N/A*

Control 10 �43 �52 �14 5 4.63 N/A*

Patient J None

Patient B None

Distance is the distance from the VWFA coordinates of (�42, �57, �15)reported by Cohen et al. (2002).*Clusters for these subjects were contiguous with other clusters outsidethe VWFA, so cluster extent could not be determined. The t threshold wasraised until the clusters separated to determine the centre of mass of the VWFA

cluster.

Figure 5 The visual word form area in control subjects and

patients. (A) In the control group, the contrast of words versus

false font strings (voxel-wise P50.005, corrected for multiple

comparisons at P50.05) revealed the visual word form area.

(B) Activation for this contrast was reduced in the patients

relative to the control subjects (voxel-wise P50.005, corrected

for multiple comparisons at P5 0.05).



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DiscussionThe goal of this study was to investigate the structural and func-

tional status of the visual word form system, including the VWFA,

in two patients with progressive alexia. Structural imaging showed

left-lateralized occipito-temporal atrophy in both patients, mild in

one (Patient J) but moderate to severe in the other (Patient B).

Functional imaging in control subjects revealed a posterior-to-

anterior gradient of selectivity for words, and all 10 showed a

functionally defined VWFA that was activated for words relative

Figure 6 The typical anterior-posterior gradient of selectivity for words in occipito-temporal cortex was abnormal in the two patients with

progressive alexia. (A–J) In all control subjects, posterior occipito-temporal cortex responded as much for false font strings as for words,

whereas more anterior regions showed greater responses to words than false font strings. This pattern was also apparent (arrowheads)

when plotting mean occipito-temporal responses in each hemisphere to words and false font strings as a function of y coordinate, as

shown in the line graphs below each image. (K and L) This selectivity gradient for words was not apparent in either of the two progressive

alexic patients. Additional slices are shown to demonstrate that both patients showed small regions that were selectively responsive to

words more dorsally in the right hemisphere. The black outlines show regions that responded more to words than false font strings

(voxel-wise P50.05) and more to words than fixation (voxel-wise P50.0001). The red outlines show regions in the two patients that

VBM showed to be atrophic (voxel-wise P5 0.005, minimum cluster extent = 1500 mm3). F = female; M = male.



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to false font strings. In contrast, neither of the two patients

showed any evidence for a selectivity gradient or for word-specific

activation of the VWFA. These findings support our hypothesis

that the visual word form system would be functionally abnormal

in progressive alexia.

Patient J showed normal bilateral occipito-temporal responses

for words relative to rest and false fonts relative to rest, whereas

Patient B showed reduced activation even in these basic contrasts.

This may be related to the degree of occipito-temporal atrophy,

which was much greater in Patient B. Because Patient B showed

abnormal activity even in basic contrasts in regions posterior to the

VWFA, it seems clear that early processing stages in the visual

word form system were implicated in his reading deficit, consistent

with the fact that his deficits extended even to the single letter

level. Patient J, in contrast, did not lack activation of regions pos-

terior to the VWFA. Rather, he lacked any emergence of select-

ivity for words. Whereas the dysfunction of his visual word form

system was more subtle than that of Patient B, regions posterior to

the VWFA may likewise be implicated as Patient J also had deficits

at the single letter level. Although our data suggest that functional

abnormalities arise posterior to the VWFA in both patients, it

should be emphasized that neither patient had severe visual per-

ceptual deficits, and object recognition was intact. Both patients’

deficits were quite specific for reading.

A crucial methodological aspect of our study was the optimiza-

tion of a paradigm that would reliably activate the VWFA in every

individual normal control subject. Otherwise, failure to detect the

VWFA in the patients with progressive alexia might simply reflect

a lack of statistical power. We used a block design with false font

control stimuli, rapid presentation, and an attentionally demanding

task in order to maximize power, minimize visual confounds, and

minimize higher level semantic processing. This design was quite

similar to that used by Vinckier et al. (2007). Our pilot testing

showed that with slower presentation rates, there was consider-

able interindividual variability presumably related to higher level

processing, and words did not necessarily activate the VWFA

more than visually matched non-word stimuli such as false fonts

or consonant strings. Others have made similar observations

(Tagamets et al., 2000; Cohen et al., 2003). Our optimized para-

digm was successful in identifying the VWFA and mapping the

posterior-to-anterior gradient of selectivity for words in all 10 of

our healthy control participants. Because of this consistency, we

can be confident that the abnormal functionality of the visual

word form system in the two patients is unlikely to reflect

normal individual variability. A direct comparison between the

two patients and the 10 control subjects provided further support

for this conclusion.

Previous functional imaging studies of the VWFA and earlier

visual processing areas in patients have shown that the VWFA

does not show typical activation for word reading or selectivity

for words when it is damaged or disconnected from its inputs

[Cohen et al., 2003, 2004 (Patient F), Henry et al., 2005;

Gaillard et al., 2006; Epelbaum et al., 2008]. Sometimes rather

precise disconnections have been demonstrated. For instance,

damage to the white matter in the splenium of the corpus callo-

sum or its continuation in the forceps major disconnects the VWFA

from right hemisphere visual processing areas, resulting in

hemialexia in the left visual field; in these patients, the VWFA is

not activated by words presented in the left visual field [Cohen

et al., 2000, 2003 (Patient D)]. Damage to earlier visual process-

ing regions in the left hemisphere does not result in alexia if right

hemisphere regions are intact and interhemispheric connectivity is

preserved; in these cases, the VWFA is activated normally [Cohen

et al., 2003 (Patient M)]. The importance of the VWFA at the

anterior endpoint of the visual word form processing stream has

been highlighted in particular by two studies. Ino et al. (2008)

reported a patient who became alexic after haemorrhage in the

vicinity of the VFWA. The patient lacked functional activity in the

VWFA, but 6 weeks later his reading had recovered, and the

VWFA showed functional activity for reading again. Tsapkini

et al. (2011) showed that VWFA-like activation was displaced

posteriorly in a patient with a left fusiform resection, resulting in

a limited reading deficit. Our two cases differ from all of these

previous cases of acquired alexia in that the VWFA was neither

completely destroyed nor deafferented by a frank structural lesion.

However, our results converge with findings of abnormal function-

ality in the visual word form system in children and adults with

developmental dyslexia, in whom there may be structural abnorm-

alities but there are no frank lesions (Salmelin et al., 1996;

Rumsey et al., 1997; McCrory et al., 2005; van der Mark et al.,

2009, 2011).

Our two patients with progressive alexia met criteria for differ-

ent clinical syndromes. Patient J likely represents an early case of

PCA, whereas Patient B met diagnostic criteria for logopenic

primary progressive aphasia. Here we consider our findings for

each patient in the context of their broader clinical syndrome.

Patient J met clinical criteria for PCA, in that his presenting dif-

ficulty was the insideous onset of a primary visual dysfunction

(Tang-Wai et al., 2004). It is not uncommon that the first visual

dysfunction in PCA is progressive peripheral alexia (Benson et al.,

1988; McMonagle et al., 2006; Mendez et al., 2007). Patient

J did not have any other significant visual or visuospatial deficits,

although he made some errors on the number location subtest

from the Visual Object and Space Perception battery, which

may be a harbinger of the emergence of a more generalized

visual impairment.

Some authors have proposed that distinct variants of PCA dif-

ferentially involve dorsal and ventral visual streams (Caselli, 1995;

Mackenzie Ross et al., 1996; Beversdorf and Heilman, 1998;

Mendez and Cherrier, 1998; Migliaccio et al., 2012) or that

there is a continuum between dorsal and ventral forms

(Lehmann et al., 2011), whereas others have argued that the

dorsal stream is generally more affected than the ventral stream

(McMonagle et al., 2006). Mendez and Cherrier (1998) reported

two cases of PCA in which alexia with letter-by-letter reading was

the first symptom, but both patients eventually developed a more

general ventral simultanagnosia and eventually dorsal simultanag-

nosia. In contrast, Mendez (2001) reported another patient with

PCA with deficits primarily affecting visual localization and visuo-

spatial integration, in whom reading was largely preserved. PET

showed bilateral occipito-parietal hypometabolism. In another pa-

tient with occipito-parietal degeneration, Vinckier et al. (2006)

showed that reading was preserved, except in situations that

make particular demands on visuospatial processing, such as



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rotated words, or words with spaces between the letters. Taken

together, these cases suggest that peripheral alexia with

letter-by-letter reading in PCA is related to dysfunction of ventral

rather than dorsal visual regions (Mendez and Cherrier, 1998;

Mendez, 2001).

Our findings with Patient J are consistent with this view. The

functional abnormalities we observed were ventral, as was the

mild structural atrophy, consistent with progressive alexia being

the only prominent symptom in this case. We concur with previ-

ous researchers that there are multiple variants of PCA depending

on the particular regions affected (Caselli, 1995; Mackenzie Ross

et al., 1996; Lehmann et al., 2011; Migliaccio et al., 2012), and

that cases in which alexia is the first and most prominent symptom

reflect a ventral variant (Beversdorf and Heilman, 1998; Mendez

and Cherrier, 1998).

Patient B met clinical criteria for logopenic primary progressive

aphasia. He showed progressive alexia with a prominent peripheral

component, as evidenced by letter-by-letter reading, as well as a

central spelling deficit, and significant aphasia. Although logopenic

primary progressive aphasia is associated with reading deficits

(Brambati et al., 2009; Henry et al., 2012), such deficits are typically

central in nature; to our knowledge, no previous cases have been

reported with significant peripheral deficits as well. Patient B’s

unique pattern of impairment can be explained in terms of his atro-

phy, which encompassed both posterior perisylvian cortex,

accounting for spoken language deficits and possibly contributing

to his spelling impairment, as well as occipito-temporal regions, ac-

counting for peripheral alexia. Patient B’s atrophy was also strongly

left-lateralized, which is consistent with his relatively spared visuo-

spatial functions. It has been suggested that PCA and logopenic pri-

mary progressive aphasia have much in common as atypical

Alzheimer’s variants, and may differ primarily in relative lateralization

of posterior atrophy (Migliaccio et al., 2009).

In conclusion, we have shown that the visual word form system

was functionally abnormal in two cases of progressive alexia,

despite the fact that the VWFA was neither completely destroyed

nor were there any frank lesions that would disconnect it from its

afferents. This functional abnormality was accompanied by sub-

stantial atrophy in only one of the two cases, indicating that

defective activation of the visual word form system resulting in

profound alexia may precede significant atrophy.

AcknowledgementsWe thank Scott Squire, Sarah Andersen, Ashley Chavez and Adam

Gendreau for assistance with functional imaging data collection,

Kate Possin for help with visuospatial assessments, Cyma Van

Petten, Elena Plante and Dianne Patterson for sharing control

structural data, three anonymous reviewers for their constructive

comments, and the individuals who participated in our study,

especially Patient J and Patient B for their time and patience.

FundingThis work was supported by the National Institutes of Health

[DC010878 to S.M.W., DC007646 to P.B., DC008286 to S.Z.R.

and P.B., AG014792 to Cyma Van Petten] and the University of

Arizona.

Supplementary materialSupplementary material is available at Brain online.

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